HjC OH Fructose

Figure 7.8 Endogenous fructose synthesis

Dietary sources

In most Western societies the main source of Fru is the disaccharide sucrose Glc a-( 1 fS2) Fru which is a pervasive sweetener I hgh fructose corn syrup is a major source in the US, where it is added to many industrial food products including ketchup and bread. The Fru content in this syrup is increased by conversion of its Glc during industrial processing using glucose isomcrase D-xvlulose ketol-isomerase (EC5.3.1.S).

Mixtures with equal amounts of monomcric Fru and Glc are 1.3 times sweeter than the same amount of sucrose (Stone and Oliver, 1969). Fruits and vegetables also contain significant amounts of monomcric Fru and sucrose. About half of the dry weight of peaches is sucrose.

Daily 1 ru intakes may be as high as lOOg. especially in populations with high intakes of sucrose and high-fructose corn syrup (Ruxton et at.. 1999). Per capita disappearance of fructose was XI g/day in the US for the year 1997 (Elliott el at.. 20(12).

Digestion and absorption

The disaccharide sucrose (Cilc «-( I >jB21 Fru) is hydrolyzed by sucrose a-glucosidase (EC3.2.1.4X i, a component of the brush border enzyme complex sucrase-isomaltase. The facilitative transporter GLUT5 (SI.C2A5), and to a lesser extent GLUT2 (SI.C2A2). mediate Fru uptake from the small-intestinal lumen, mainly the jejunum (Helliwell etat.. 20(H)).

Both of the facilitative transporters GLUTS (SLC2A5) and GLUT2 (SLC2A2) mediate Fru uptake from the small-intestinal lumen (Helliwell et at.. 2000). Diffusion and paracellular passage via glucose-activated solute drag also may contribute to absorption. Large quantities (25 g) are poorly absorbed and will cause malabsorption symptoms in as many as one-third of healthy subjects (Born et at.. 1994). GLUT2 (SLC2A2) facilitates the transport of Fru out of entcrocytes into interstitial fluid from where it joins the portal blood.

The mixed oligosaccharidesraffinose (Gal «-(I >6) Glc ¿H 1 >fi2) Fru), siachyosc (Gal a-(l>6) Gal <H I >6) Glc rr-( I >02) Fru), and verbascose (Gal ot-(l>6) Gal a-(l>f>) Gal «-(1 >f>) tile «-(1 >¡32} Fru) in beans. peas, and other plant-derived foods are not digestible in humans and may cause abdominal distention and flatulence due to bacterial metabolism. Melezitose (Glc (*-(!>?) Fru or-Cilc) and luranose

figure 7.9 lnrcstin.il abwirptitm of (rurtujc

(Glc a-(l>3) Fru), minor constituents of conifer-derived honey, are additional exaples of Fru-containing oligosaccharides to w hich humans may be exposed. Use of oral u-galactosidasc (EC3.2.1.22) along w ith a meal can initiate the digestion of these oligosaccharides ((iantats el of., 1994).

1 he indigestible carbohydrates (dietary tiher) inulin and various smaller oligofiructose species are composed of 0(2-1 Ifructose-fructosy 1 chains with a minor contribution of glucose residues (Fiamm eial.. 2001). Inulin from chicory roots consists of about 10-20 fructose residues, oligofructoses contain fewer than l(J fructose residues. Microflora, especially bifidobacteria, of the dislal ileum and colon thrive on these indigestible carbohydrates. The bacterial breakdown generates short-chain fatty acids that arc utilized by local cnicrocytes (mainly bulyrate) or transported to the liver (mainly acetate and propionate 1.

Transport and cellular uptake

Blood circulation: Fru is transported in blood as a serum solute. The concentration in plasma of healthy people is around 0,13mmol I. and increases in response to very high Fru intakes (Hallfriseh el id.. 1986). Fru is taken up into cells \ ia the facilitate e transporters GLUT2 (Colville eial., IW3) and GLUT5. Uptake of Fru into spermatozoa depends on GLUTS.

Blood-brain barrier: There is no evidence that significant amounts of Fru cross from blood into brain.

Maierno fetal transfer: The net transfer of Fru to the fetus is unknown, but is likely to lie small.


Most Fru is metabolized in the liver, which explains some of the metabolic differences between Fru and glucose, I he dominant metabolic pathway proceeds \ ia fructose t-phosphate and joins the glycolysis pathway at the level of the trioses giyceraldehyde 3-phosphate and di hydroxy acetone phosphate. A smaller proportion joins the glycolysis pathway immediately through the phosphorylation to the glycolysis intermediate fructose 6-phosphate by magnesium-dependent hexokinase (LC2.7.1.1). Another significant proportion of ingested fructose can be directly conv erted into glucose v ia sorbitol (Kawaguchi et a!.. 14%).

Catabolism viafivctose 1 phosphate: Ketohexokinase (hepatic fructokinase. FX' in liver and in pancreatic islet cells phosphorylates Fru to fructose I-phosphute. Fructose-bisphosphate aldolase (aldolase. E.C4.1.2.I3) cleaves both fructose I-phosphate and the glycolysis intermediate fructose 1,6-bisphosphate. There are three genetically distinct isoforms of this crucial enzyme: aldolase A predominantly in muscle, aldolase 13 in liver, and aldolase C in brain. People with a lack of aldolase II cannot metabolize Fru properly {hereditary fructose intolerance), Giyceraldehyde is phosphorylated by triokinase (EC2.7.I.2K).Triosephosphate isomcrase (EC5.3.I.I) converts dihydroxyacelone phosphate into giyceraldehyde 3-phosphate. which can then continue along the glycolytic pathway or contributes to gluconeogenesis depending on prevailing conditions.

ch-oh I

ch-oh I




Aldehyde feduclsso (sulfate)

L-lditoi L*NAD

2-deTiydr f

(zmcl NNADH







Henokrnase or Glucokiitsse (magnesium)


ho-ch ch-oh

Glucose 6-phospfiale h?c—oh c=o ho-ch I

ch-oh I

ch-oh I


Hexokinase (magnesium r


KWohexo-f kinase L

ch-oh I

Fructose t -phosphate h2c-oh c=o ho-ch I



oh phcsphofrucio-

ch-oh I


Fructose 6-phosphate Fructose t ,6-bisphosptiate ch-oh

oh ho-chj

D ¡hydro xyacetone phosphate ho-chj

D ¡hydro xyacetone phosphate


bisphosohnte aldolase hc I

ch-oh I

H2C-OH Glyceraldehyde hjc-o—p-oh oh

Fructose 6-phosphate Fructose t ,6-bisphosptiate

Tm>kinase (magnesium 1

Glyceraldehyde 3-phosphate

Tm>kinase (magnesium 1

Glyceraldehyde 3-phosphate

Figure 7.10 Fructose mi is bo I ism

The sorbitol pathway: The zinc-containing L-iditol 2-dehydrogenase (sorbitol dehydrogenase, ECl.1.1.14) converts small amounts of Fru to sorbitol, which can then he oxidized to Glc by NADP-dependent aldehyde reductase (aldose reductase. ECl. 1,1.21 >.


[ here is no .sigmlicant specific accumulation of Fru that could be mobilized in times of need.


Very little net loss of Fru occurs in healthy people even when consumption is 100 g or more Significant amounts of the plasma solute Fru are tillered in the renal glomerulus.

Most of the Fru in renal ultraliltrate is recovered from the proximal renal tubular lumen through the facilitative transporter GLUTS (Sugawara-Yokoo et ul.. 1999) and returns into the bloodstream via CLUT2.


Absorption via GLUT2 at the luminal side ofthe enterocyte is rapidly and strongly uprcgulated in response to feeding and humoral factors 11 lelliwcll et ul.. 2000). StrcsN and possibly hyperglycemia increase GLUT2 trafficking to the brush border membrane within minutes through activation of p3S MAP kinase signaling. Growlh factors, insulin and other factors also influence the Fru absorption.

Insulin enhances transcription ofthe aldolase B gene, and glucagon suppresses its tr.inscription. The latter exerts us action by binding to a cAMP-responsivc element in the promoter region (Takano et at.. 2000).

The metabolism of Fru to pyruvate (glycolysis) is not subject to the regulatory factors that act on phosphofructokinasc-1 and that play a great role in regulation of Glc metabolism. Small amounts of Fru have been suggested to improve control of Glc metabolism (Hawkins et ul., 2002). On the other hand, high Fru levels can promote hcxosamine synthesis and thereby slow iosuiin-dependent Glc utilization in muscle and adipose tissue (Wuw ul„ 2001).


Energy fuel: The complete oxidation of Fru yields about 4 kcalg and requires adequate supplies of thiamin, riboflavin, niacin, lipoate. ubiquinone, iron, and magnesium. Unspecific precursor: All metabolizablc sugars can provide carbons for numerous endogenously generated compounds such as amino acids (e.g.. glutamate from the Krebs cycle intermediate alpha-kctogiutaratc), cholesterol I from acetyl-coenzyme A), or the glycerol in triglycerides.

Hcxosamtnes: Fru is a precursor for glucosamine 6-phosphatc synthesis by gluta-mine:fiructose-6-phosphate transaminase isomerizing (GFAT: HC2.6.1.16). N-acetyl glucosamine and other hexosamines are formed after the initial rate-limiting GFAT reaction, Fhe addition of O-linked N-acetyl glucosamine to proteins can modify their signaling function and give them roles in nutrient sensing (Hanover, 2001). Fru- (and GlcHderived hexosamines are critical constituents of glycans (chondroitins. kenuans. dermatans, hyaluronan, heparans, and heparin) in the extracellular matrix of all tissues.


Born P. Zech J. Stark M. Classen M, Lorenz R. ZuekcraustauschstoOe: Vergleichende Untersuchung zur intestinalen Resorption von Fructose. Sorbit und Xyl it. Med Klin 1994:89:575-8

Colvilte CA. Scatter MJ. Jess TJ. Gould GW. Thomas HM. Kinetic analysis of the liver-type (GLUT2) and brain-type (GLUT3) glucose transporters in Xenopus oocytes: substrate specificities and effects of transport inhibitors. HioehemJ 1993;290:701-6 Elliott SS. Keitn NL. Stern JS. TelTK. Havel PJ. Fructose, weight gain, and the insulin resistance syndrome, Am J Clin Nutr 2002;7G:911-22

Flamm G. Glinsmann W, Kritchevsky D. Prosky L, Roberfroid M. lnulin and oligofructosc as dietary liber: a review of the evidence. Crit Rev Food Sei \'urr 2(H) 1:41:353 62 Ganiats TU. Nor cross WA. Halvcrson AL. Buribrd PA. Palinkas LA. Does Beano prevent gas? A double-Wind crossover study of oral alpha-galaetosidase to treat dietary oligosaccharide intolerance. JFam Pract 1994;39:441 5 I lall frisch J. I I two od K. Michaelis OL 4th, Reiser S, Prnther FS. Plasma fructose, uric acid and inotganic phosphorus responses of hyperinsulinemic men fed fructose. J Am Coll Nutr 19X6:5:61 8

Hanover JA. Glycan-dependent signaling: O-Iinked N-acetylglucosamine. FASF.B J2O01: 15:1X65-76

Hawkins M, Gabriely I. Wo/niak R. Vilcu C. Shamoon H. Rossetti L. Diabetes 2002:51: 606 14

Helliwell PA. Richardson M, Affleck J, Kellett CI. Regulation ofGI I T5. GLLIT2 and intestinal brush border fructose absorption by the extracellular signal-regulated kinase. p3X mitogen-activated kinase and phosphaiidvltnositol 3-kinase intracellular signalling pathways: implications for adaptation to diabetes. Bun hem ,/2(HM);350:163 9 Kawaguchi M. FujiiT. Kamiya Y. ItoJ. Okada M, Sakuma N, Fujinami T Fffects of fructose ingestion on sorbitol and fructose 3-phosphate contents of erythrocytes from healthy-men I eta Diaheto11996;33:100-2 Ruxton CH, Chirceau FJ, Cottrell RC, Guidelines for sugar consumption in Europe: is a quantitative approach justified? Eur J Clin Nutr 1999;53:503-13 Stone II, Oliver SM. Measurement of the relative sweetness of selected sweeteners and sweetener mixtures. J Food Sei 1969:34:215 22 Sugawara-Yokoo M, Suzuki f. Matsuzaki T. Naruse I, Takata K. Presence of fructose transporter GLL f5 in the S3 proximal tubules in the rat kidney. Kidney- im 1999:56:1022 X TakanoY, luehi V. [to J, Otsu k. Kuzumaki T, Ishikaw a K. Characterization of the responsive elements to hormones in the rat aldolase B gene. Arch Bioehem Bio/ilm 2<H)0; 377:5X 64

Wu G. Haynes TB. Van W, Meininger CJ. Presence of g I utamine: fructosephosphate amidotrans(erase for glucosamine-6-phosphate synthesis in endothelial cells: effects of hyperglycemia and glutaminc. Diabetologia 2001:44:196 202

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